Thursday, August 25, 2011

Grow taller by inhibiting PTEN?

LSJL has no effect on PTEN(at least over or under threshold) and PTEN is a PI3K pathway inhibitor. LSJL stimulates the PI3K pathway so if anything that inhibits PTEN increases height then that could mean that stimulating the PI3K pathway increases height which would support height increasing applications of LSJL.

"PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a phosphatidylinositol triphosphate 3-phosphatase that counteracts phosphoinositide 3-kinases. VO-OHpic is an extremely potent inhibitor of PTEN with nanomolar affinity in vitro and in vivo. Inhibition of recombinant PTEN by VO-OHpic is fully reversible. Both K(m) and V(max) are affected by VO-OHpic, demonstrating a noncompetitive inhibition of PTEN. The inhibition constants K(ic) and K(iu) were determined to be 27 ± 6 and 45 ± 11 nM, respectively."

"PTEN hydrolyses the phosphate group in the 3′ position from phosphatidylinositol 3,4,5-triphosphate (PIP3) to form phosphatidylinositol 4,5-biphosphate and, in doing so, is counteracting phosphoinositide 3-kinases (PI3K). The balance of PTEN and PI3K activities determines the cellular PIP3 levels, which in turn is recognised by other signalling components such as Akt"

We used mice deficient in a negative regulator of PI3K signaling, the tumor suppressor, Pten.

Pten gene deletion in osteo-chondrodroprogenitors was obtained by interbreeding mice with loxP-flanked Pten exons with mice expressing the Cre recombinase under the control of the type II collagen gene promoter (Pten(flox/flox):Col2a1Cre mice).

Pten(flox/flox):Col2a1Cre mice exhibited both increased skeletal size, particularly of vertebrae, and massive trabeculation accompanied by increased cortical thickness. Primary spongiosa development and perichondrial bone collar formation were prominent in Pten(flox/flox):Col2a1Cre mice, and long bone growth plates were disorganized and showed both matrix overproduction and evidence of accelerated hypertrophic differentiation (indicated by an altered pattern of type X collagen and alkaline phosphatase expression). Consistent with increased PI3K signaling, Pten-deficient chondrocytes showed increased phospho-PKB/Akt and phospho-S6 immunostaining, reflective of increased mTOR and PDK1 activity. No significant change in growth plate proliferation was seen in Pten-deficient mice, and growth plate fusion was found at 6 months."

"Specific ligand—receptor interactions recruit PI3K into proximity with its substrate, phosphatidylinositol(4,5)-bisphosphate, PI(4,5)P2, to generate the “second messenger,” PI(3,4,5)P3. The phosphatidylinositol 3′-phosphatase, Pten (phosphatase and tensin homolog deleted on chromosome 10), a well-known tumor suppressor, reverses the effects of PI3K by dephosphorylating PI(3,4,5)P3 at the D-3 position, to yield PI(4,5)P2"

"By 15 wk of age, Ptenflox/flox:Col2a1Cre mice were an average of 1.15 times longer than control mice"

"Femoral lengths [from] Ptenflox/flox:Col2a1Cre femurs were 1.07 times longer than those of control mice"

"in contrast to wildtype mice whose epiphyseal growth plates do not fuse with age, the tibial growth plates of Ptenflox/flox:Col2a1Cre mice were fused by 6 mo of age"

"Compared with controls, expression of type X collagen protein in 1-wk-old Ptenflox/flox:Col2a1Cre mouse growth plates was not only increased but was also more widespread, with expression of this protein encroaching well into the proliferative zone"

"Ptenflox/flox:Col2a1Cre mice [had] 13% increase in body length caused by the enlargement of vertebrae and intervertebral disk spaces[so this can increase spinal height in adults without inducing new growth plates]. Interestingly, long bones only exhibited a 4.6% increase in the Ptenflox/flox:Col2a1Cre mice"

"Chondrocytes within the growth plates acclimatize themselves to a variety of stresses that might otherwise disturb cell fate. The tumor suppressor PTEN (phosphatase and tensin homolog deleted from chromosome 10) has been implicated in the maintenance of cell homeostasis. We have created chondrocyte-specific Pten knockout mice (Pten(co/co);Col2a1-Cre) using the Cre-loxP system. Following AKT activation, Pten mutant mice exhibited dyschondroplasia[a mass of hypertrophic cartilage] resembling human enchondroma[a cartilage bone marrow cyst]. Cartilaginous nodules originated from Pten mutant resting chondrocytes that suffered from impaired proliferation and differentiation, and this was coupled with enhanced endoplasmic reticulum (ER) stress. ER stress in Pten mutant chondrocytes only occurred under hypoxic stress, characterized by an upregulation of unfolded protein response-related genes as well as an engorged and fragmented ER in which collagens were trapped. An upregulation of hypoxia-inducible factor 1alpha (HIF1alpha) and downstream targets followed by ER stress induction was also observed in Pten mutant growth plates and in cultured chondrocytes, suggesting that PI3K/AKT signaling modulates chondrocytic adaptation to hypoxic stress via regulation of the HIF1alpha pathway."

"The HIF1α/VEGF axis supports chondrocyte survival in the interior growth plate, where oxygen tension is much lower than in the exterior region. In addition, this axis may also modulate chondrocytic size and proliferation, cartilaginous matrix accumulation and blood vessel invasion during endochondral bone formation"

"At postnatal day (P) 40, the tails of mutant mice were 11-14% longer than those of PtenCo/+;Col2a1-Cre and Pten+/+;Col2a1-Cre controls". However the length of the bones of the temur and tibia were the same.

"The non-hypertrophic chondrocytes that extended into the bone marrow cavity began to proliferate ectopically and to exhibit hypertrophy, gradually forming a proliferating pseudo-growth plate within the bone marrow cavity"

"The proliferation of Pten mutant chondrocytes was in fact decreased in the neoplastic core as compared with controls"

"The upregulation of BiP, together with the downregulation of Ppr Ihh and Col10a1, indicated that ER stress was triggered upon Pten deletion in chondrocytes and resulted in decreased differentiation."

"ER stress was significantly increased in Pten mutant chondrocytes under conditions of hypoxia, suggesting that a PTEN deficiency together with hypoxia synergistically triggers ER stress and subsequent de-differentiation of Pten mutant chondrocytes."

"the activation of the PI3K/AKT pathway in chondrocytes might serve multiple functions during the progression of hypoxia-induced ER stress; it perturbs the ER but may save the cell. As a consequence, dysplastic chondrocytes develop."<-So PTEN may cull the herd of weak chondrocytes.

"Inactivation of HIF1α in chondrocytes leads to increased cell death, accelerated proliferation and reduced yield of Vegf, Pgk and p57Kip2"

"inactivation of murine von Hippel-Lindau tumor suppressor protein (VHL) in chondrocytes causes enlarged cell size, accumulation of ECM, decreased proliferation and increased expression of Vegf, Pgk and p57Kip2 through a mechanism that facilitates the stabilization and accumulation of HIF1α protein"

"We have generated chondrocyte specific PTEN deletion mice using Col2a1Cre and PTEN(loxp/loxp) mice. PTEN mutant mice are viable and fertile, nonetheless, develop kyphosis over time. Histological analyses show mutant vertebrae and intervertebral discs are larger and therefore the spines are longer than in control mice. In addition, the growth plates are thicker, invading trabecular bone areas are deeper, and marrow adipocyte populations are higher in PTEN mutant mice. Furthermore, the growth plates, not normally fused in mouse long bones, are fused in PTEN mutants."

"PTEN is required for maintaining normal growth plate structures in older mice."<-Mice with loss of PTEN had growth plate fusion at 5-8 months.